Abstract

Background. Signaling through the B cell receptor appears to be a major contributing factor in the pathogenesis of chronic lymphocytic leukemia. Toll-like receptors bridge the innate and adaptive immune response by acting as co-stimulatory signals for B-cells. The available data on Toll-like receptors expression in chronic lymphocytic leukemia are limited and derive from small series of patients.

Design and Methods. We profiled the expression of Toll-like receptors signaling pathway-associated genes in 192 chronic lymphocytic leukemia cases and explored potential associations with molecular features of the clonotypic B cell receptor.

Results. Chronic lymphocytic leukemia cells express all Toll-like receptors expressed by normal activated B cells, with high expression of TLR7 and CD180, intermediate of TLR1, TLR6, TLR10 and low of TLR2 and TLR9. The vast majority of adaptors, effectors and members of the NFKB, JNK/p38, NF/IL6 and IRF pathways are intermediately-to-highly expressed, while inhibitors of Toll-like receptors activity are generally low-to-undetectable, indicating that the Toll-like receptors signaling framework is competent in chronic lymphocytic leukemia. Significant differences were identified for selected genes between cases carrying mutated vs. unmutated IGHV genes or assigned to different subsets with stereotyped B cell receptors. The differentially expressed molecules include receptors, NFκB/MAPK signaling molecules and final targets of the cascade.

Conclusions. The observed variations are suggestive of distinctive activation patterns of the Toll-like receptors signaling pathway in subgroups of chronic lymphocytic leukemia cases defined by B cell receptor molecular features. Additionally, they indicate that different or concomitant signals acting through receptors other than the B cell receptor can affect the behavior of the malignant clone.